JPS6213922B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a compound represented by the following formula (wherein A represents a linear or branched alkylene having 1 to 3 carbon atoms) or a salt thereof (hereinafter referred to as the present compound).
The present invention relates to a cataract treatment agent containing as an active ingredient. The present compound is a known compound with extremely low toxicity and sputum-dissolving action, and the present inventors have discovered that the present compound is also useful as a cataract therapeutic agent. Many researchers have long found that the level of reduced glutathione in the cataractous lens is markedly reduced and protein SH groups are also reduced, and it has been thought that there is a relationship between cataract progression and lens or systemic SH substances. Ta. In fact, among SH substances, topical administration of glutathione and oral administration of tiopronin are used to prevent the progression of cataracts. In general, in the search for cataract therapeutic agents, there are experimental systems using mice with genetic cataracts as well as experimental cataracts induced by drugs such as galactose and naphthalene. The effect of delaying cataract onset was investigated as an indicator. We also investigated the therapeutic effects on cataracts in dogs.
It was revealed that this compound is useful as a cataract therapeutic agent. Next, the content of the present invention will be described based on examples. Example 1 Effect of delaying the onset of galactose cataract (in vitro test) Lenses from male Wistar rats weighing 150 to 200 g were removed, placed one by one in a petri dish, and mixed with TC199 bicarbonate buffer medium containing 30 mM galactose (Nichisui). (manufactured by Nippon Steel & Co., Ltd.) and cultured at 37°C in a warmer with 5% carbon dioxide gas passed through. 10 mM 3-mercaptopropionyl-L-cysteine was added to the lenses of the first group (10 lenses), and no drug was added to the lenses of the other group (10 lenses) as a control. The control lens became cloudy with increasing number of days of culture;
On the seventh day, the entire surface of the lens cortex became cloudy. In drug-treated lenses, even on the 7th day, there was not a single case in which the entire cortex became cloudy, and only vacuole formation around the equator or partial cortical clouding was observed. At the same time, increases in water and sodium and decreases in potassium were suppressed in drug-treated lenses, results consistent with macroscopic observation of lens opacity. Example 2 Effect of delaying cataract onset on galactose cataract (in vivo test) Using Wistar male rats weighing 48 to 50 g,
The effect of 3-mercaptopropionyl-L-cysteine on galactose cataract was investigated. The experiments were conducted using 10 animals per group, which were divided into the following two groups. Group A: 30% galactose-added food group B: 30% galactose-added food mixed with 1% 3-mercaptopropionyl-L-cysteine As a result, the crystalline lenses of rats in all experimental groups were visually observed. The number of days for complete clouding was 29 days for Group A and 51 days for Group B, indicating that this compound had the effect of delaying the onset of galactose cataract. Example 3 Effect of delaying cataract onset in mice with congenital cataracts (in vivo test) Cat Nakano mice with congenital cataracts raised for generations were used. 3-Mercaptopropionyl-L-cysteine once a day at a certain time from 2 weeks after birth
A dose of 0.5 mg/g was injected into the abdomen, a control group was similarly administered physiological saline, and an untreated group was set up to conduct a simple comparison of cataract development among the three groups. Table 1 shows the age of onset of lens opacity and the number of animals affected.
The average age of cataract onset was 31.3 days, 27.5 days, and 27.9 days in the drug administration group, physiological saline administration group, and no treatment group, respectively.

[Table] Example 4 Canine cataract treatment test 5% for cataract dog (7 years old, male, weight 8.8 kg)
One drop of 3-mercaptopropionyl-L-cysteine eye drops was instilled into both eyes five times a day. At the beginning of the test, the test dog's left eye showed a slight pupillary reflex and a slight net was observed. A pupillary reflex was observed in the right eye, but the entire lens was cloudy with a bimantic white opacity. Three weeks after instillation, the patient was no longer bumping into objects while walking and no longer missed steps on the stairs at home, but no changes in the crystalline lens were observed. 10 weeks after starting eye drops, the area around the lens in the left eye is 2-3 mm.
Transparency can be seen in the width, and the center is also slightly transparent.
Compared to when the test started, netting became clearly visible. Pupillary reflexes also became normal. In the right eye, clearing was observed around the lens, and the opacity of the lens was fading throughout. Toxicity test 3-Mercaptopropionyl-L of the present compound
- Acute toxicity tests on cysteine showed low toxicity with an LD ₅₀ of 957mg/Kg. In addition,
Dixon's up and down method was used to calculate LD ₅₀ . (Experimental Animals) Twelve ddY:std male mice (body weight 20.1 to 24.4 g) were used. (Test solution and administration method) After neutralizing and dissolving the sample by adding equimolar 1N NaOH, the sample was adjusted to a concentration of 10% with distilled water for injection. Administration was performed by injecting into the tail vein of mice at a rate of 0.25 ml/min. As is clear from the above tests, this compound is useful as a cataract therapeutic agent. The dosage is systemic administration, and when used for adult treatment, 10 to 1000 mg per day depending on the route of administration and number of doses.
The route of administration is oral, subcutaneous or intravenous injection. Also, for local administration,
0.1-10% eye drops or eye ointments can also be used. When the composition of the present invention is for internal use, formulations such as tablets, capsules, and powders are suitable from the viewpoint of a dosage form suitable for absorption from the gastrointestinal tract and ease of administration. For this purpose, binders such as gelatin, sorbitol, polyvinylpyrrolidone, etc., excipients such as lactose,
Starches, calcium phosphate, etc., lubricants, such as magnesium stearate, talc, etc., disintegrants, such as calcium carboxymethyl cellulose, etc. may contain conventional additives, and injections may be prepared as such or as an aqueous solution of a salt such as sodium Formulations are preferred. Further, as a base for eye drops or eye ointments, a normal physiological saline solution, a buffer solution such as borate or phosphate, or an ointment or cream such as petrolatum is used. In the case of eye drops, it is desirable to use a combination of tablets, granules, powder, etc., which are dissolved before use, and a solution. The following is an example of the composition of the formulation example: (1) Oral preparation (a) Tablet This compound 100 mg Ethyl cellulose 50 mg Crystalline cellulose 80 mg Carboxymethyl cellulose 7 mg Magnesium stearate 3 mg Total 240 mg This tablet is coated with a film that is commonly used. There is no problem with adding sugar, and sugar coating can also be performed. (b) Granules 100mg of this compound Polyvinylpyrrolidone 25mg Lactose 365mg Talc 10mg total 500mg (c) Powder 100mg of this compound Lactose 500mg Starch 370mg Colloidal silica 30mg total 1000mg (d) Capsules 100mg of this compound Lactose 32mg Crystalline cellulose 56mg colloidal Silica 2mg total 190mg (2) Injection This compound is an aqueous solution (PH6.5-7.0) containing 250mg of this compound in 5ml. (3) Eye drops When using, dissolve the following two tablets in 5 ml of solution. Tablets Compound 125mg Sodium benzoate 5mg Total 130mg Solution Sodium hydroxide 0.36g Benzalkonium chloride 0.005g Sterile purified water Dosage meter 100ml Eye drops are made airtight by adding an inert gas or an antioxidant. It can also be prepared by filling a container.

Claims (1)

[Scope of Claims] 1. A cataract therapeutic agent containing a compound represented by the following formula (wherein A represents a linear or branched alkylene having 1 to 3 carbon atoms) or a salt thereof as an active ingredient.